Donanemab Slows Progression of Earlier, Less Severe Alzheimer's Disease
Several immunotherapies targeting amyloid-β in the brain have now been shown to modestly slow the progression of Alzheimer's disease if applied at an earlier stage of the condition. This is a long way removed from a cure, particularly given the potentially severe side-effects that accompany brain-targeted monoclonal antibody therapies. Alzheimer's is a complicated condition, and it seems clear that removing amyloid-β does too little on its own to reduce pathology in the brain. It is contributing, but it is not the only contribution, or perhaps not even the most important contribution. More will be needed in parallel, such as also targeting inflammatory microglia, or removing pathological tau aggregates, or restoring vascular function that is impaired by aging in many patients with neurodegenerative conditions.
Donanemab is a monoclonal antibody, like the two earlier Alzheimer's drugs, aducanumab (Aduhelm) and lecanemab (Leqembi). These drugs attack plaques in the brain that are made of a protein called amyloid. They disrupt cell function and lead to the rapid spread of another protein called tau. Both amyloid and tau contribute to the development of Alzheimer's disease.
The trial showed donanemab slowed cognitive decline by 35% compared with placebo in patients with low-to-intermediate levels of tau in the brain. These results are similar to those reported with Leqembi, which received FDA approval earlier this month. In the donanemab trial, patients also experienced a 40% lower risk of progressing from mild cognitive impairment to mild dementia, or from mild-to-moderate dementia.
Donanemab was better at removing amyloid plaques compared to Aduhelm and Leqembi. It reduced tau concentrations in the blood, but not in a key area of the brain. While these results are encouraging, an in-depth analysis still is needed to understand how these findings affect patient outcomes. Patients with more advanced disease showed little to no benefit compared to those who received the placebo. Like the two other new Alzheimer's drugs, donanemab was associated with ARIA, amyloid-related imaging abnormalities that may include brain swelling and microbleeds. Serious ARIA occurred in 3.7% of patients, including three deaths. Risks were higher among patients with the APOE4 gene, which is related to an increased risk for Alzheimer's.